Norwalk-like viruses (NLVs) are single-stranded, positive-sense RNA viruses that cause acute gastroenteritis in humans. The viruses are highly contagious, resistant to environmental conditions, and spread quickly by surface contact or person-to-person transmission. NLVs commonly cause large food- and water-borne outbreaks in a variety of settings, both civilian and military. NLVs have been difficult to study due to the lack of cell culture and animal models. There is no treatment available for NLV infection and the high genetic and antigenic diversity of NLVs makes it difficult to prevent the disease by a vaccination. We have recently observed that the prototype Norwalk virus (NV) uses the human histo-blood group antigens as receptors for infection. This discovery opens a way to develop strategies to control NLV disease. Extended studies showed that different NLVs recognize different receptors defined by secretor, Lewis, and ABO types. Glycoconjugates containing these major histo-blood epitopes were found to be responsible for NLV binding and similar glycoconjugates found in human milk protected breast-fed infants from NLV infection. Thus, human histo-blood group antigens play a critical role in the host specificity to NLV infection. Inhibitors that block NLV attachment/entry to intestinal epithelial cells may be developed as an effective antiviral drug against NLVs. Towards this future goal, the following three specific aims are proposed. Specific aim 1. To characterize the genetic variability of Norwalk-like viruses (NLVs) and their binding to human histo-blood group antigens for extended strain diversity. Specific aim 2. To map the domain(s) of NLV capsids that bind to human histo-blood group antigens by computer modeling and biochemistry approaches. Specific aim 3. To determine the crystal structure of NLV capsid and sub-capsid units in the presence and absence of human histo-blood group antigens.